DESCRIPTION (Applicant's Description): The TEL-PDGFBetaR fusion protein was identified as the protein product of a t(5;12) translocation in a patient with chronic myelomonocytic leukemia. The protein fuses the amino portion of TEL with the transmembrane and cytoplasmic domains of the PDGFBetaR. TEL, a member of the ETS family of transcription factors, has subsequently been described as a common site of rearrangement in multiple forms of leukemia. The applicants show, in the Preliminary Results, that TEL-PDGFBetaR transforms I L 3 dependent Ba/F3 cells to factor independence. TEL-PDGFBetaR in transfected Ba/F3 cells and patient samples encodes an approximately 100 kDa protein which is constitutively tyrosine phosphorylated. Analysis of in vitro translated TEL-PDGFBetaR shows that an amino terminal TEL domain, which is highly conserved among some ETS family members, mediates dimerization of TEL-PDGRBetaR. They hypothesize that dimerization mediated by the TEL domain of T E L - PDGFBetaR leads to constitutive PDGFBetaR kinase activation and transformation of cells. Consistent with this hypothesis, transformation by TEL-PDGFBetaR requires the oligomerization domain in TEL and the kinase activity of the PDGFBetaR. They propose to study the transforming capability of the TEL-PDGFBetaR fusion protein in detail and to characterize its mechanisms of transformation. In Specific Aim 1, they will use in vitro systems to study the functional effects of exogenous expression of TEL-PDGFBetaR. In particular, they will describe the signaling pathways activated by the TEL-PDGFBetaR fusion protein and, through the use of point mutations in the critical tyrosines within the PDGRBetaR portion of the protein, determine which signaling pathways are necessary and sufficient for transformation in vitro. In Specific Aim 2, they will develop in vivo models of CMML. They will use bone marrow transplantation models to test the in vivo transforming ability of TEL-PDGFBetaR and to analyze the importance of mutations identified as functionally relevant in vitro. In addition, they will develop an animal model of CMML by expressing TEL-PDGRBetaR under the control of a myeloid specific promoter in transgenic animals. These in vivo models will further test the transforming ability of the fusion protein and allow exploration of potential therapies for CMML.